Treatment of depression and ptsd

ABSTRACT

Depression and PTSD are treated by administration of hCG, or an hCG analog, or a prodrug or metabolite of hCG or an hCG analog, in an amount equivalent to a subcutaneous dose of 50-200 IU, preferably 120-170 IU, more preferably 140-160 IU, of hCG per day.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/268,979, filed on Sep. 19, 2016, which is a continuation applicationof U.S. patent application Ser. No. 14/436,172, filed on Apr. 16, 2015,which is a National Stage application under 35 U.S.C. X371 ofInternational Application No. PCT/US2013/065711, having an InternationalFiling Date of Oct. 18, 2013, which claims the benefit of priority toU.S. Provisional Application No. 61/715,590, filed on Oct. 18, 2012. Thedisclosure of the prior application is considered part of (and isincorporated by reference in) the disclosure of this application.

BACKGROUND OF THE INVENTION Field of the invention

This invention relates to the treatment of depression and post traumaticstress disorder (PTSD).

Description of the Related Art Chronic Pain, Central Sensitization, andMood Disorders

An ongoing and pervasive problem in the medical community is treatingpatients with chronic pain syndromes. It is well recognized today thatchronic pain is fundamentally different from acute pain, also referredto as nociceptive pain, that results from a mechanical, chemical,metabolic or inflammatory insult. Central sensitization is a newlyrecognized diagnostic entity that underlies a broad range of phenotypicsyndromes, including various chronic pain and mood disorders. Centralsensitization refers to an abnormal state of functioning of the neuronsand circuitry of the central pain intensity, perception and modulationsystems; due to synaptic, chemical, functional and/or structuralchanges, in which pain is no longer coupled, as acute nociceptive painis, to particular peripheral stimuli. Instead, the central nervoussystem (CNS) initiates, maintains and contributes to the generation ofpain hypersensitivity and perception even in the absence of a peripheralstimulus. See, for example, C J Woolf, “Central sensitization:Implications for the diagnosis and treatment of pain”, PAIN, v. 152, pp.S2-S15 (2011).

Chronic pain and central sensitization represent an overlappingconstellation of diagnostic conditions and syndromes. This may explainwhy there remains a critical lack of effective medical interventions totreat chronic pain disorders. Traditional pharmaceutical approachesgenerally deal with a single involved pathway, which tends to yield lessthan ideal results and is often associated with significant toxicity.For example, the treatment options most commonly investigated to dateconsist of centrally acting drugs. These include ketamine,dextromethorphan, gabapentin, pregabalin, duloxetine, milnacipran,lamotrigine; and not all of these have reached human trials at thistime. Each has demonstrated a poor therapeutic index in trials.

It has been noted that major depressive disorder (MDD) and chronic painsyndrome often present as co-morbid conditions: 30-60% of cases in onereport (M J Bair et al., “Association of depression and anxiety aloneand in combination with chronic musculoskeletal pain in primary carepatients”, Psychosomatic Medicine, v. 70(8), pp. 890-897 (2008)). Arecent review on this topic suggests that there may be a sharedneurobiological basis of MDD, fibromyalgia, neuropathic pain, and otherchronic pain syndromes (V Maletic et al., “Neurobiology of depression,fibromyalgia and neuropathic pain”, Frontiers in Bioscience, v. 14, pp.5291-5338 (2009). Robert Post first proposed that ‘kindling’ andsensitization may have similar neurobiological underpinnings, such asneuroplastic changes and alterations in gene expression (R M Post,“Kindling and sensitization as models for affective episode recurrence,cyclicity, and tolerance phenomenon”, Neuroscience & BiobehavioralReviews, v. 31(6), pp. 858-873 (2007)).

Depression and Post Traumatic Stress Disorder

Depression, as discussed here, represents two disorders: dysthymicdisorder (DD), classified in the DSM-IV-TR (Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, Text Revision, AmericanPsychiatric Association, Washington D.C., 2000) under code 300.4 (seeDSM-IV-TR at pages 345-348 and 376-381), and major depressive disorder(MDD), classified in the DSM-IV-TR under code 296.3x (see DSM-IV-TR atpages 349-356 for a description of major depressive episode and pages369-376 for MDD). Diagnostic criteria for DD are, in summary, (1) adepressed mood for most of the day for more days than not for at least 2years; (2) the presence, while depressed, of symptoms such as sleepdisturbances, fatigue, and feelings of hopelessness; (3) no continuousperiod of more than 2 months during the 2 years without the symptoms in(1) and (2); and no major depressive episode present in the first 2years of the disturbance (i.e. so that the disorder is not betteraccounted for by MDD); diagnostic criteria for MDD are, in summary, thepresence of at least one major depressive episode (the presence of 5 ormore symptoms including at least one of depressed mood and loss ofinterest or pleasure present during the same 2-week period, representinga change from previous functioning; the symptoms causing clinicallysignificant distress or impairment, and not due to the effects of asubstance, medical condition, or bereavement) not better accounted forby other conditions and lack of manic, mixed, or hypomanic episodes. Asthe DSM-IV-TR notes (page 374), DD and MDD are differentiated based onseverity, chronicity, and persistence, and “the differential diagnosisbetween them is made particularly difficult by the fact that the twodisorders share similar symptoms . . . ”. Depression is commonlypharmacologically treated with antidepressants (such as the selectiveserotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptakeinhibitors (SNRIs), and norepinephrine/dopamine reuptake inhibitors(NDRIs)), and also with the atypical antidepressants, tricyclicantidepressants, or monoamine oxidase inhibitors (MAOIs), or othermedications, generally if the SSRI/SNRI/NDRI antidepressants areunsuccessful.

Post traumatic stress disorder (PTSD) is an anxiety disordercharacterized by the re-experiencing of an extremely traumatic eventaccompanied by symptoms of increased arousal and by the avoidance ofstimuli associated with the trauma, classified in the DSM-IV-TR undercode 309.81 (see DSM-IV-TR at pages 429 and 463-468). Diagnosticcriteria for PTSD are, in summary, that (1) the person has been exposedto a traumatic event in which both the person experienced, witnessed, orwas confronted with one or more events that involved actual orthreatened death or serious injury or a threat to physical integrity andthe person's response involved intense fear, helplessness, or horror;(2) the event is persistently re-experienced; (3) there is a persistentavoidance of stimuli associated with the trauma and numbing of generalresponsiveness (not present before the trauma); and (4) there arepersistent symptoms of increased arousal (not present before the trauma)indicated by at least two of (i) difficulty falling or staying asleep,(ii) irritability or outbursts of anger, (iii) difficulty concentrating,(iv) hypervigilance, and (v) exaggerated startle response. PTSD iscommonly pharmacologically treated with antidepressants (such as theSSRIs and SNRIs) and anxiolytics, sometimes acutely treated withantipsychotics, and insomnia and nightmares are sometimes treated withprazosin (an adrenergic α-blocker).

The usual pharmacological treatments for depression and PTSD areassociated with a number of side effects, in particular the sexual sideeffects known with SSRIs and SNRIs, that may make them unattractiveoptions for persons suffering from these disorders.

Pain Transmission and G-Protein Coupled Receptors

Pain transmission and modulation through the central nervous systemnetwork of neurons and support glial cells (microglia and astrocytes) islargely under the control of a large family of cellular receptors knownas G-protein-coupled receptors (GPCRs). The function of these complextransmembrane receptors is to transduce extracellular stimuli intointracellular signaling including gene transcription. GPCRs modulateand/or mediate virtually all physiologic processes in eukaryoticorganisms, including acute and chronic pain. An estimated 90% of allknown GPCRs are expressed in the central nervous system. 80% of thecurrently proposed GPCR families have a known role in modulation ofpain. Similarly, most of the identified genes associated with painmodulation are GPCR related genes (L S Stone et al., “In search ofanalgesia: Emerging role of GPCRs in pain”, Molecular Interventions, v.9(5), pp. 234-241 (2009)).

In the pharmaceutical development industry, the search for new analgesicand mood modulating targets has its foundation in establishing centralnervous system receptor groups for which ligands can be identified,leading to the manufacture of pharmaceutical compounds to provide painrelief and mood improvement. Regarding analgesia, there are for example,several recognized GPCR sub- groups that have been established astemplates for drug development. Opioid receptors, cannabinoid receptors,GABA receptors, and α2 adrenergic receptors are examples of suchestablished receptors for analgesic drug development.

Human Chorionic Gonadotropin (hCG) and the LH/hCG Receptor

Human chorionic gonadotropin (hCG) is a is a hormone produced duringpregnancy that is made by the developing placenta after conception, andlater by the placental component syncytiotrophoblast. hCG shares areceptor with Luteinizing Hormone (LH), the LH/hCG receptor. Thisreceptor is a GPCR. Both hormones are produced in the same cells in thepituitary gland. Both LH and hCG are produced continually throughoutlife in males and females.

hCG is now recognized to have pleiotropic actions throughout the body asevidenced by the documented presence of receptors for hCG in multiplecellular compartments including the central nervous system (CNS). See CV Rao, “An overview of the past, present, and future of non-gonadalLH/hCG actions in reproductive biology and medicine”, Seminars inReproductive Medicine, v. 19, pp. 7-17 (2001), and Z M Lei et al.,“Neural actions of luteinizing hormone and human chorionicgonadotropin”. Seminars in Reproductive Medicine, v. 19, pp. 103-109(2001).

In the adult CNS, hCG receptors have been established to be present inthe hippocampal formation, hypothalamus, cerebral cortex, brain stem,cerebellum, pituitary gland, neural retina, spinal cord and theependymal region (Z M Lei et al., “Novel expression of human chorionicgonadotropin/luteinizing hormone receptor gene in brain”, Endocrinology,v. 132, pp. 2262-2270 (1993). Both neurons and glial cells are shown toexpress receptors for hCG (Z M Lei et al., previously cited). It hasbeen postulated that hCG may play an important signaling role indifferentiation and development of tissue subsets from germ celllayering during the blastocyst stage (M J Gallego et al., “The PregnancyHormones HCG and Progesterone Induce Human Embryonic Stem CellProliferation and Differentiation into Neuroectodermal Rosettes”, StemCell Research and Therapy, v. 1, p. 28 (2010)) to organ developmentduring fetal life (M A Abdallah et al., “Human Fetal Non-Gonadal TissuesContain HCG/LH Receptors”, Journal of Clinical Endocrinology andMetabolism, v. 89, pp. 952-956 (2004)) and perhaps on some more subtle,yet clinically significant way, in adults. Recent evidence confirms thepresence of hCG receptors in the adult CNS, and additional evidencesupports hCG as a signaling hormone for tissue differentiation andgrowth. See C V Rao et al., “The past, present and future of non-gonadalLH/hCG actions in reproductive biology and medicine”, Molecular andCellular Endocrinology, v. 269(1-2), pp. 2-8 (2007).

As noted above, the luteinizing hormone/human chorionic gonadotropin(LH/hCG) receptor is a GPCR (L S Stone et al., previously cited). It hasbeen specifically shown to complex with the Gαi/o group resulting inmodulation of neurotransmission (L Hu et al., “Essential role of Gprotein-gated inwardly rectifying potassium channels ingonadotropin-induced regulation of GnRH neuronal firing and pulsatileneurosecretion”, Journal of Biological Chemistry, v. 281(35), pp.25231-25240 (2006)). Gαi/o proteins mediate the widespread inhibitoryeffects of many neurotransmitters and they mediate the effects of almostall analgesic GCPR agonists (L S Stone et al., previously cited). D.Puett et al., “Structure-Function Relationships of the LuteinizingHormone Receptor”, Annals of the New York Academy of Science, v. 1061,pp. 41-54 (2005), describe the LH/hCG receptor (which they refer to asthe luteinizing hormone receptor) and studies on elucidating themechanisms by which LH and hCG bind to it and activate it. They alsodescribing transfected cells containing both wild-type and mutatedLH/hCG receptors, and a single chain hCG-LH/hCG receptor complexcontaining a fusion protein of the two subunits of hCG linked to theLH/hCG receptor. X-L Meng et al., “Human Chorionic Gonadotropin InducesNeuronal Differentiation of PC12 Cells through Activation of StablyExpressed Lutropin/Choriogonadotropin Receptor”, Endocrinology, v.148(12), pp. 5865-5873 (2007), describe the transfection of the LH/hCGreceptor into PC12 cells (a cell line extensively used for studyingneuronal differentiation) that then stably express the receptor, andstudies in those cells when treated with hCG or LH and optionalinhibitors. Various techniques for evaluating the interaction betweenthe LH and hCG ligands and the PC12 cells are described.

Pain Management with hCG

In a series of applications including U.S. Provisional Application No.61/475,908, filed 15 Apr. 2011; U.S. application Ser. No. 13/211,101,filed 16 Aug. 2011; and U.S. application Ser. No. 13/311250, “Methodsfor Chronic Pain Management and Treatment Using hCG”, filed 5 Dec. 2011,there are described methods, etc. for the treatment of chronic pain orother central sensitization sequelae by the administration of hCG or itsanalogs or metabolites at doses equivalent to the subcutaneousadministration of hCG at 50-200 IU/day, and 120-170 IU/day, preferably140-160 IU/day.

The applications report that patients discontinued other analgesicagents and manifested a continued and improved analgesic response,confirming that another receptor group was indeed engaged to create theclinical response noted in that series. For example, the sedation,tolerance (requiring higher dosing for effect), constipation andaddiction potential seen with chronic opiate administration was not seenin patients discontinuing opiate administration in favor of continuedhCG administration, implying a different mechanism of action at adifferent analgesic receptor site for these patients.

The applications also suggest that hCG acts similarly on neural pathwaysinvolved in MDD that are subject to a very similar sensitization or‘kindling’ phenomenon (implying that each episode of depression makessubsequent depressive episodes more likely and less dependent upon anexternal stimulus such as stress or sickness), where cellular structureand function are modulated and modified through many of the same CNSsynaptic, cell signaling and transcriptional pathways, to effectdepression.

The disclosures of the documents referred to in this application areincorporated into this application by reference.

SUMMARY OF THE INVENTION

In a first aspect, this invention is a method of treating at least oneof depression and post traumatic stress disorder in a person sufferingtherefrom, comprising administering a compound that is hCG, or an hCGanalog, or a prodrug or metabolite of hCG or an hCG analog, to theperson, in an amount equivalent to a subcutaneous dose of 50-200 IU,preferably 120-170 IU, more preferably 140-160 IU, of hCG per day.

In other aspects, this invention thus includes:

-   (1) a method of treating at least one of depression and post    traumatic stress disorder in a person suffering therefrom,    comprising administering a composition containing a compound that is    hCG, or an hCG analog, or a prodrug or metabolite of hCG or an hCG    analog, to the person, in an amount equivalent to a subcutaneous    dose of 50-200 IU, preferably 120-170 IU, more preferably 140-160    IU, of hCG per day;-   (2) the use of a compound that is hCG, or an hCG analog, or a    prodrug or metabolite of hCG or an hCG analog, in an amount    equivalent to a subcutaneous dose of 50-200 IU, preferably 120-170    IU, more preferably 140-160 IU, of hCG per day, or a composition    containing such compound, for the treatment of at least one of    depression and post traumatic stress disorder;-   (3) a kit containing a compound that is hCG, or an hCG analog, or a    prodrug or metabolite of hCG or an hCG analog, or a composition    containing such compound, with instructions to administer the    compound or composition in an amount equivalent to a subcutaneous    dose of 50-200 IU, preferably 120-170 IU, more preferably 140-160    IU, of hCG per day; and-   (4) a method of prescribing or supplying to a person suffering from    a condition that is at least one of depression and post traumatic    stress disorder a treatment for that condition that comprises    administering a composition containing a compound that is hCG, or an    hCG analog, or a prodrug or metabolite of hCG or an hCG analog, to    the person, in an amount equivalent to a subcutaneous dose of 50-200    IU, preferably 120-170 IU, more preferably 140-160 IU, of hCG per    day.

In other aspects this invention also includes:

-   (5) treating at least one of depression and post traumatic stress    disorder in a person suffering therefrom by activating the central    nervous system LH/hCG receptor; and-   (6) treating at least one of depression and post traumatic stress    disorder in a person suffering therefrom by modulating the central    sensitization pathway.

Preferred embodiments of this invention are characterized by thespecification and by the features of claims 2 to 18 of this applicationas filed. In particular, for each of the other aspects, the preferencesare to be taken as the same as those expressed in the specification andclaims for the first aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Human chorionic gonadotropin” or “hCG” includes both hCG obtained fromthe urine of pregnant women (uHCG) and hCG prepared in bacterial, yeast,plant, or mammalian cell cultures utilizing recombinant DNAhybridization techniques (rHCG).

An “hCG analog” is a compound having the biological activity of hCG inthe treatment of depression and/or post traumatic stress disorder andthat is either: (i) a modified hCG (such as a truncated, elaborated, orchemically modified—as by amino acid substitution—hCG), or (ii) acompound that can bind to the LH/hCG receptor to produce the same effectas hCG.

A “prodrug” of hCG is hCG modified such that the modified hCG isconverted within a target cell or target organ/anatomic structure intohCG so as to achieve the effect of hCG administration; a prodrug of anhCG analog is similarly defined. For example, conversion of contemplatedcompounds into prodrugs may be useful where the active drug is too toxicfor safe systemic administration, or where the contemplated compound ispoorly absorbed by the digestive tract or other compartment or cell, orwhere the body breaks down the contemplated compound before reaching itstarget. Thus, it should be recognized that the compounds according tothe invention can be modified in numerous manners, and especiallypreferred modifications include those that improve one or morepharmacokinetic and/or pharmacodynamic parameters. For example, one ormore substituents may be added or replaced to achieve a higherbioavailability.

A “metabolite” of hCG is a compound resulting from in vivo metabolism ofhCG (for example, via proteolytic digest, glycosylation, hydroxylation,phosphorylation, sulfuration, etc), where the metabolite produces theeffect of hCG administration; a metabolite of an hCG analog is similarlydefined.

“Comprising” or “containing” and their grammatical variants are words ofinclusion and not of limitation and mean to specify the presence ofstated components, groups, steps, and the like but not to exclude thepresence or addition of other components, groups, steps, and the like.Thus “comprising” does not mean “consisting of”, “consistingsubstantially of”, or “consisting only of”; and, for example, aformulation “comprising” a compound must contain that compound but alsomay contain other active ingredients and/or excipients.

“Treating” or “treatment” of a condition includes one or more of:

-   (1) inhibiting development of the condition, e.g., arresting its    development,-   (2) relieving the condition, e.g., causing regression of or curing    the condition,-   (3) preventing recurrence of the condition, and-   (4) palliating symptoms of the condition.

Salts

Salts (for example, pharmaceutically acceptable salts) of the compoundsof this invention (i.e. hCG, or an hCG analog, or a prodrug ormetabolite of hCG or an hCG analog) are included within the compounds ofthis invention and are useful in the compositions, methods, and usesdescribed in this application. Such salts are preferably formed withpharmaceutically acceptable acids. See, for example, Stahl and Wermuth,eds., “Handbook of Pharmaceutically Acceptable Salts”, (2002), VerlagHelvetica Chimica Acta, Zürich, Switzerland, for an extensive discussionof pharmaceutical salts, their selection, preparation, and use. Unlessthe context requires otherwise, reference to any compound of thisinvention is a reference both to the compound and to its salts.

These salts include salts that may be formed when acidic protons presentare capable of reacting with inorganic or organic bases. Typically theparent compound is treated with an excess of an alkaline reagent, suchas hydroxide, carbonate or alkoxide, containing an appropriate cation.Cations such as Na+, K+, Ca2+, Mg2+ and NH4+ are examples of cationspresent in pharmaceutically acceptable salts. Suitable inorganic bases,therefore, include calcium hydroxide, potassium hydroxide, sodiumcarbonate and sodium hydroxide. Salts may also be prepared using organicbases, such as salts of primary, secondary and tertiary amines,substituted amines including naturally-occurring substituted amines, andcyclic amines including isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and the like.

If a compound contains a basic group, such as an amino group, it may beprepared as an acid addition salt. Acid addition salts of the compoundsare prepared in a standard manner in a suitable solvent from the parentcompound and an excess of an acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid (giving the sulfate and bisulfatesalts), nitric acid, phosphoric acid and the like, and organic acidssuch as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, salicylic acid,4-toluenesulfonic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, lactic acid, 2-(4-hydroxybenzoyl)benzoicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,gluconic acid, 4,4′-methylenebis(3-hydroxy-2-naphthoic)acid,3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid,laurylsulfuric acid, glucuronic acid, glutamic acid,3-hydroxy-2-naphthoic acid, stearic acid, muconic acid and the like.

Compositions and Dosing

Pharmaceutical compositions comprising the compounds of this inventioninclude a compound that is hCG, or an hCG analog, or a prodrug ormetabolite of hCG or an hCG analog, and optionally a pharmaceuticallyacceptable excipient.

The compounds may be administered by any route suitable to the personbeing treated and the nature of the person's condition. Routes ofadministration include administration by injection, includingintravenous, intraperitoneal, intramuscular, and subcutaneous injection,by transmucosal or transdermal delivery, through topical applications,nasal spray, suppository and the like or may be administered orally.Formulations may optionally be liposomal formulations, emulsions,formulations designed to administer the drug across mucosal membranes ortransdermal formulations. Suitable formulations for each of thesemethods of administration may be found, for example, in Remington: TheScience and Practice of Pharmacy, 20th ed., A. Gennaro, ed., LippincottWilliams & Wilkins, Philadelphia, Pa., U.S.A. Typical formulations willbe either oral or solutions for injection, especially subcutaneousinjection. Typical dosage forms will be tablets or capsules for oraladministration, solutions for injection, and lyophilized powders forreconstitution as solutions for injection.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, preferably in unit dosage form suitable for single administrationof a precise dosage. In addition to an effective amount of the activecompound(s), the compositions may contain suitablepharmaceutically-acceptable excipients, including adjuvants whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. “Pharmaceutically acceptable excipient”refers to an excipient or mixture of excipients which does not interferewith the effectiveness of the biological activity of the activecompound(s) and which is not toxic or otherwise undesirable to thesubject to which it is administered.

For solid compositions, conventional excipients include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. Liquid pharmacologically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in water or an aqueous excipient, such as, for example, water,saline, aqueous dextrose, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliaryexcipients such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc.

For oral administration, the composition will generally take the form ofa tablet (including an orally-disintegrating tablet) or capsule, or itmay be an aqueous or nonaqueous solution, suspension or syrup. Tabletsand capsules are preferred oral administration forms. Tablets andcapsules for oral use will generally include one or more commonly usedexcipients such as lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. Orally-disintegratingtablets will generally include excipients such as mannitol or anothersugar as the primary diluent, a disintegrating agent such ascrospovidone or gelatin, and microcrystalline cellulose. When liquidsuspensions are used, the active agent may be combined with emulsifyingand suspending excipients. If desired, flavoring, coloring and/orsweetening agents may be added as well. Other optional excipients forincorporation into an oral formulation include preservatives, suspendingagents, thickening agents, and the like.

Injectable formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions or liposomalformulations. The sterile injectable formulation may also be a sterileinjectable solution or a suspension in a nontoxic parenterallyacceptable diluent or solvent. Among the acceptable vehicles andsolvents that may be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils, fatty estersor polyols are conventionally employed as solvents or suspending media.

The pharmaceutical compositions of this invention may also be formulatedin lyophilized form for parenteral administration. Lyophilizedformulations may be reconstituted by addition of water or other aqueousmedium and then further diluted with a suitable diluent prior to use.The liquid formulation is generally a buffered, isotonic, aqueoussolution. Examples of suitable diluents are isotonic saline solution, 5%dextrose in water, and buffered sodium or ammonium acetate solution.Pharmaceutically acceptable solid or liquid excipients may be added toenhance or stabilize the composition, or to facilitate preparation ofthe composition. Typically, a pharmaceutical composition of the presentinvention is packaged in a container with a label, or instructions, orboth, indicating use of the pharmaceutical composition for the treatmentof depression and/or post traumatic stress disorder and indicatingdosing in an amount equivalent to a subcutaneous dose of 50-200 IU,preferably 120-170 IU, more preferably 140-160 IU, of hCG per day. Thedosing may be determined based on once/day dosing of the compound ormore frequent dosing, but will preferably be based on once/day or atleast not more than twice/day dosing, as a matter of patientconvenience.

A person of ordinary skill in the art will have no difficulty,considering that skill and this disclosure, in determining appropriatedosing for a compound that is hCG, an hCG analog, or a prodrug ormetabolite of hCG or an hCG analog, by administering such a compound toa person suffering from depression or post traumatic stress disorder;and will also have no difficulty, considering that skill and thisdisclosure, in formulating compositions of the compounds for such use.

hCG itself is available, by prescription in the United States, inlyophilized powdered form in 5,000 IU or 10,000 IU vials forreconstitution from various sources under brand names such as NOVAREL®(Ferring Pharmaceuticals), PREGNYL® (Organon), and others.

Treatment of Depression and Post Traumatic Stress Disorder

In the first aspect, this invention is a method of treating at least oneof depression and post traumatic stress disorder in a person sufferingtherefrom, comprising administering a compound that is hCG, or an hCGanalog, or a prodrug or metabolite of hCG or an hCG analog, to theperson, in an amount equivalent to a subcutaneous dose of 50-200 IU,preferably 120-170 IU, more preferably 140-160 IU, of hCG per day.

The treatment preferably comprises once/day administration of thecompound, such as by a once/day subcutaneous injection of hCG at a doseof 50-200 IU, preferably 120-170 IU, more preferably 140-160 IU; but maycomprise administration more frequently of divided doses of the compoundin an amount equivalent to a subcutaneous dose of 50-200 IU, preferably120-170 IU, more preferably 140-160 IU, of hCG per day.

In a study of 24 persons treated with 150 IU/day of hCG subcutaneouslyfor 6 weeks for weight loss (14 persons) or pain control (10 persons)reported in application Ser. No. 13/311250 referred to previously,patients were assessed with the DoloTest™, a test instrument used toassess pain and health-related quality of life issues. See K Kristiansenet al., “Introduction and Validation of DoloTest: A Health RelatedQuality of Life Tool Used in Pain Patients”, Pain Practice, v. 10(5),pp. 396-403 (2010); and see also www.dolotest.dk. There werestatistically significant improvements in scores relating to depressivesymptoms (reduced energy and strength, low spirit, reduced social life,and problems sleeping) over the group, indicating the usefulness of hCG,and expected use of its analogs and prodrugs and metabolites, for thetreatment of depression. In addition, a small number of personssuffering from PTSD treated by the inventors with hCG in the same mannerdisplayed an improvement in their PTSD symptoms.

No hCG gonadal treatment-associated side effects were observed; and nohCG-related effects are expected at this low dose. Notably, in the aboveseries patients who had been placed on antidepressant medications formood disorders and/or chronic pain syndromes at the time of initiatinghCG treatment, no longer required these medications after initiating hCGtreatment, and were free of untoward side effects associated with thesemedications. For example, one patient had previously been placed onLEXAPRO® (escitalopram oxalate, an SSRI) for depression and struggledwith anorgasmia associated with taking this medication. On hCG treatmentand no longer needing to take LEXAPRO®, this patient reported clearimprovement in mood and a return to orgasmic function, which has been ofsignificant value to him. These responses imply the activation of analternate receptor group in the action of hCG in treating depression andPTSD.

Although improvement in symptoms may be seen rapidly, and though somepersons treated for pain control did not require continuing treatmentbeyond their initial 6 week course of treatment, most did; and theinventors expect that treatment for depression and/or PTSD willtypically last at least 1 week, preferably at least 3 weeks, morepreferably at least 6 weeks, and will generally be continuing/chronic,with administration of the compound daily. As with other antidepressanttreatments, it is possible that patients treated chronically for a longtime (for example, months or more) may be able to terminate hCGtreatment without a recurrence of their symptoms, and this may be testedon a case-by-case basis in a manner consistent with normal medicalpractice: if there is a relapse on cessation of treatment, the treatmentmay be resumed and will be effective again.

Although age, gender and weight of recipients of hCG treatment forchronic pain and weight loss does not appear with current studies toaffect the preferred therapeutic ranges, it is contemplated that theamount of compound that is administered and the dosage regimen fortreating a disease condition with the compounds and/or compositions ofthis invention for treating at least one of depression and posttraumatic stress disorder may depend on one of more of a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may vary.

While this invention has been described in conjunction with specificembodiments and examples, it will be apparent to a person of ordinaryskill in the art, having regard to that skill and this disclosure, thatequivalents of the specifically disclosed materials and methods willalso be applicable to this invention; and such equivalents are intendedto be included within the following claims.

1-18. (canceled)
 19. A method of treating an anxiety disorder in asubject that has experienced a serious injury, comprising administeringto the subject hCG at a subcutaneous dosage of 50 IU per day to 200 IUper day or a dosage equivalent to a subcutaneous dosage amount of 50 IUper day to 200 IU per day, wherein the method of treating includestreating at least one symptom of the anxiety disorder.
 20. The method ofclaim 19, wherein the anxiety disorder is a disorder that includes asymptom of avoiding stimuli associated with the serious injury.
 21. Themethod of claim 19, wherein the anxiety disorder is a disorder thatincludes a symptom of re-experiencing one or more events related to theserious injury.
 22. The method of claim 19, wherein the anxiety disorderis post traumatic stress disorder.
 23. The method of claim 19, whereinthe method comprises activating the central nervous system LH/hCGreceptor.
 24. The method of claim 19, wherein the hCG is administered asa subcutaneous dosage of between 120 IU per day and 170 IU per day ofhCG.
 25. The method of claim 19, wherein the hCG is administered as adosage equivalent to a subcutaneous dosage amount of between 120 IU perday and 170 IU per day of hCG.
 26. The method of claim 19, wherein thehCG is administered as a subcutaneous dosage of between 140 IU per dayand 160 IU per day of hCG.
 27. The method of claim 19, wherein the hCGis administered as a dosage equivalent to a subcutaneous dosage amountof between 140 IU per day and 160 IU per day of hCG.
 28. The method ofclaim 19, wherein the hCG is administered once per day.
 29. The methodof claim 19, wherein the hCG is administered once daily for at least 1week.
 30. The method of claim 19, wherein the hCG is administered oncedaily for at least 3 weeks.
 31. The method of claim 19, wherein the hCGis administered once daily for at least 6 weeks.
 32. The method of claim19, wherein the hCG is administered chronically.
 33. The method of claim19, wherein the hCG is administered as a subcutaneous dosage thatconsists essentially of hCG.
 34. A method of activating the centralnervous system LH/hCG receptor in a subject, comprising administering tothe subject hCG at a subcutaneous dosage of 50 IU per day to 200 IU perday or a dosage equivalent to a subcutaneous dosage amount of 50 IU perday to 200 IU per day.
 35. The method of claim 34, wherein the hCG isadministered as a subcutaneous dosage of between 120 IU per day and 170IU per day of hCG.
 36. The method of claim 34, wherein the hCG isadministered as a dosage equivalent to a subcutaneous dosage amount ofbetween 120 IU per day and 170 IU per day of hCG.
 37. The method ofclaim 34, wherein the hCG is administered as a subcutaneous dosage ofbetween 140 IU per day and 160 IU per day of hCG.
 38. The method ofclaim 34, wherein the hCG is administered as a dosage equivalent to asubcutaneous dosage amount of between 140 IU per day and 160 IU per dayof hCG.